The Pharmaceutical R&D Model is Broken. Here’s How to Fix It

3/5/10

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for sale, they would simply invest in other industries (e.g. software) that had a much shorter time frame to product launch as well as a significantly lower cost of entry into the industry. Because of this, the investors are then looking for an acquisition or an IPO. These events generally will not occur before a company has its drug in clinical trials, and demonstrated some really solid evidence that it is safe and effective. As a result, many investors (i.e. VC firms) will only provide money if the entrepreneurs can get their drug into clinical trials in a period of 18 to 24 months.

So is this time frame possible? Absolutely. It happens all the time. With many molecular targets, a drug can be found, manufactured at small scale under exacting conditions, and be declared ready to enter the clinic. This early stage is where the critical choices get made, often with little or no data. There are so many decisions to make. Defining the basic biology experiments. Choosing the ultimate composition of the molecule. Establishing a manufacturing process. Biological testing in multiple species. Stability testing. Analytics to define uniformity. Toxicology. The success rate for a drug making it through clinical trials is only about 7 percent. I’ve heard many people blame the FDA for the current low rate of drug approvals. They say they’re too conservative, too focused on safety.

I’d like to propose an alternate interpretation of the data. Drugs are currently failing in clinical trials at a high rate because they enter clinical testing before they are truly ready. And drugs, like people, usually get but a single chance to make a good first impression with both the FDA and investors. Fail in the clinic once as a new drug, and you are done for.

The current approach is simply a formula for failure for biotech startups. This recipe mixes equal parts hubris, financial pressure, and unresolved scientific/medical questions that are whipped together to form half-baked drugs that are poorly understood, designed, and vetted. Cutting corners to save money often backfires. Those of you who have tried to do your own plumbing or electrical work know the meaning of the phrase “the cheap comes out expensive” when you need to hire a pro to fix your mistakes. The drug development process is no different, but is vastly more expensive to repair.

There’s no getting around it: biomedical research is very expensive. So how do we pay for drug discovery research going forward, if Big Pharma doesn’t want to pay for it, and smaller companies can’t always afford to as a result of their limited funding? New approaches are required. Getting the federal government to pay for this doesn’t seem like a viable path; it’s not their job, and they’re already financially constrained (i.e. broke). Industry has been testing out two other approaches in the past few years: shipping research offshore, and establishing agreements with contract research organizations. Can these approaches get the job done?

I’m afraid I have reservations about both of these efforts to boost research productivity. Offshore jobs will certainly be cheaper, but the countries that are getting most of these jobs (e.g. China, India) don’t have a strong record of novel drug development, and quality control is a serious concern. Contract research organizations that perform critical tasks for a fee, but don’t take equity in a drug, can free a biotech company from hiring/firing cycles, as well as provide expertise not available in a small company. There would seem to be some merit to that approach. My concern here, … Next Page »

Stewart Lyman is Owner and Manager of Lyman BioPharma Consulting LLC in Seattle. He provides strategic advice to clients on their research programs, collaboration management issues, as well as preclinical data reviews. Follow @

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  • Ty

    Very good analysis on the problems, yet mere tax incentive is a kinda weak solution. What we need is a whole new biotech eco system. The long and single-threaded pipeline should be disected. Discovery companies should be focusing on validating novel disease/target concepts in animal and able to ‘sell’ the newly discovered target/lead. There should be a separate breed of companies with expertise in ‘lead optimization’ that turns the lead into a viable clinical candidate that can be ‘sold’. And development companies take over and proceed with clinical trials and registration. The first group sells the science. Second group compounds and the third drugs. It’s not too unlike Intel sells chips, MS sells Windows, and HP sells PCs. Why ROI is too long in pharma industry? Because we perceive ‘a drug’ as the only ‘product’. We need to change that perception.

  • Steve S

    If one of the problems of drug trial failure rates and wasted money is that small companies are pressured to move ideas to quickly into the clinic – how do you rate the so called new discipline of “translational medicine” where the whole idea is to get “drug candidates” into people with as little development as possible? (and I suspect is also a mechanism where Med Schools can gain access to a large previously untapped source of revenue!)

  • Simon

    Great analysis of the problem, but agree that tax incentives may not be enough. Although it is a good start. Bridging the “valley of death” or the period between proof of concept in animals and filing an IND is still the biggest problem for start-up biopharma. So-called “seed and early-satge funds” are now wanting phase 2 data. (Sorry VCs, but I’m going straight to big pharma with decent phase 2a data!)

  • http://robertmatthews.org Robert Matthews

    Great overview. Picking up on the point made by Ty, it seems to me that there are strong grounds for scepticism about current animal models. My own research (see http://tinyurl.com/ygm6dtc) suggests their false positive and false negative rates are so high that they contribute no predictive weight of evidence to subsequent performance in human RCTs. We really need these models either validated (which may well be very hard and expensive to do), or abandoned in favour of something better (eg microdosing, human tissue culture etc).

  • http://www.hustonassociates.net Mike

    Excellent overview and subsequent commentary. I have considerable experience with start ups as a consultant. The trends I have witnessed are CEO’s more focused filing an IND for whatever they can rather admitting that some drugs should never see the clinic. I also agree with Robert. Animal models (even for safety) are not very predictive. Translational medicine does have a chance to improve our “hit” rates, but most biomarkers are in the process of being validated and lag the availability of potential therapeutics. There will be convergence over the next 3-5 years.

  • Marc

    Insightful analysis. However missing some key points on the numbers.
    Yes one can pick 5 startups/pre-revenue companies who had a product approved in a given year. But the important stat is the denominator: how many comparable companies did not have a product advance, let alone file or get approved?
    Large pharmas are indeed advancing multiple compounds in multiple therapy areas, simultaneously. The startups do not have that luxury or capacity. The reported costs, $2.7 Billion per approved drug, reflect those allocated to failed and successful programs. Given the benchmarks of approx 10% success from IND to launch, that translates to roughly $270 Million / approved drug, which does not seem that far off the mark.
    Large pharma certainly does have its issues, and I’m not one to rush to its defense. But when stats are invoked to support a position, they need to be used carefully or they can detract from the inferences.

  • http://www.lymanbiopharma.com Stewart Lyman

    Thank you all for taking the time to share your thoughts. I agree that more reforms are needed besides the tax incentive for five-year minimum biotech investments, but that was the best idea that I could come up with that I could actually envision being put into practice relatively rapidly. I was hoping others would respond to my commentary with a variety of novel ideas as to how this R&D problem might be solved. In response to Ty’s comment, I heard a seminar just this week by Clive Stanway, CSO of Cancer Research Technology in the UK. His organization, in fact, represents the first third of what Ty is proposing: they do the preclinal research and then sell it off for a royalty to pharma companies to develop. Reconfiguring an entire industry, as Ty suggests doing, would be extremely difficult to accomplish (in the short term) given the inertia of the member companies. Look how long it took pharma to embrace biotechnology. As for Steve S’s comment, my sense of the term “translational medicine” is to imply adding resources directed at moving discoveries from the bench into the clinic. I do not associate this with “as little development as possible” although others may think of it that way. Translational medicine should benefit both the public and pharma/biotech by increasing the transfer rate of discoveries into potential medicines. Simon, any novel ideas how to bridge the “valley of death”? As to Robert’s comments, many people want to get rid of animal models because they are expensive (especially when you step up to primates), time consuming, and not always predictive. However, the industry is still waiting for an acceptable substitute that does better. If this were an easy problem to solve, someone would have already done so. I agree with Mike that useful biomarkers are still being validated, and while I think it is clear that many of these will be quite helpful in sorting patients with particular diseases (e.g. cancer) into different groups for dosing with distinct drugs, this approach may not work for many afflictions that result from a wide spectrum of molecular determinants. Finally, in response to Marc, the numbers I picked were not meant to be statistics. They were merely chosen to illustrate certain points. The “$2.7 billion dollars spent per new drug developed” number is clearly wrong; small companies never have anywhere near that kind of money, and the large ones clearly never spend anything close to that. Finding out true numbers in this area is exceedingly difficult. It is easy to determine the number of clinical trials being conducted in the US. However, many of these are not for new molecular entities, but instead are for new indications for old drugs, or new dosing modalities (different formulation, dose, route of administration, syringe design, etc.). Pharma, of course, counts all of this money spent as drug development R&D expense (which it is), but let’s be clear: this is not money spent on the discovery of new drugs. Small companies will, almost by definition, have a success rate of zero, fifty, or one hundred percent because they will only have one or two drugs in development.

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